There is a fundamental gap in understanding how changes in frontal lobe function that emerge in middle age contribute to aging-related deficits in cognitive flexibility. Continued existence of this gap represents an important problem because, until it is filled, understanding how functional and structural changes that occur during normal aging contribute to deficits in cognitive decline will remain unclear. The long-term goal is to determine how neurobiological changes in the frontal lobe contribute to cognitive decline during normal aging. The objective of this proposal is to investigate aging-related neuronal changes in discrete sub-regions of medial prefrontal cortex (mPFC) to better understand how they impact cognitive decline during normal aging. Extinction of trace fear conditioning is an excellent model for these studies because middle-aged and aged rats exhibit pronounced deficits that parallel distinct aging-related changes within the infra-limbic (IL) and pre-limbic (PL) sub-regions of mPFC. The central hypothesis is that aging-related extinction deficits correlate with differential expression of activity and plasticity markers in IL and PL, and that region-specific modulation of plasticity mechanisms will alleviate these extinction deficits. This hypothesis has been formulated based on preliminary data produced in the applicant's laboratory. The rationale for the proposed research is that knowledge of the underlying plasticity deficits that accompany aging-related extinction impairments will provide critical data necessary for determining the underlying mechanisms of aging-related frontal lobe dysfunction and the development of targeted strategies to improve cognitive function in the elderly. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify plasticity mechanisms underlying aging- related extinction deficits; and 2) Identify a candidate mechanism that ameliorates aging-related extinction deficits. Under the first aim, proven western blot and patch-clamp recording approaches, which have been established as feasible in the applicants' hands, will be used to study changes in immediate-early gene expression and intrinsic excitability in mPFC of behaviorally characterized adult, middle-aged, and aged rats. Under the second aim, a proven mPFC cannulation approach, established as feasible in the applicant's hands, will be used to specifically increase the excitability of IL neurons, and thus explore candidate mechanisms for aging- related extinction deficits. The approach is innovative because it combines aging-related deficits in extinction learning with immediate-early gene and intrinsic excitability measurements to investigate early, aging-related changes in mPFC function. The proposed research is significant because it is expected to vertically advance and expand understanding of how aging-related changes in activity-dependent gene expression can interact with intrinsic neuronal excitability to produce measurable deficits in extinction learning that emerge in middle age. Ultimately, such knowledge has the potential to inform the development of neurobiologically-based strategies for treating aging-related frontal lobe dysfunction and improving quality of life for the elderly.